The protein-protein interaction (PPI) between the transcription factor p53 and its negative regulator Mdm2 is a major target in current cancer drug discovery. Disrupting the interaction between p53 and Mdm2 was shown to restore the wild type p53 activity and drive cancer cells selectively into apoptosis.1 Many investigations of small molecule p53-Mdm2 antagonists in different cancer cell lines and animal models support their usefulness as potential anticancer agents with a novel mode-of-action. While several classes of small molecule p53-Mdm2 antagonists have been described in the literature, only a few compounds are of sufficient potency and have been structurally characterized. See Czarna, A.; Beck, B.; Srivastava, S.; Popowicz, G. M.; Wolf, S.; Huang, Y.; Bista, M.; Holak, T. A.; Dömling, A. Angew. Chem. Int. Ed. 2010, 49, 5352-5356, and Popowicz, G. M.; Dömling, A.; Holak, T. A., Angew. Chem. Int. Ed 2011, 50, 2680-2688.
Protein-protein interaction antagonists are described to be challenging targets for small molecule drug discovery due to their often extended and rather flat interfaces. However, the interface between p53 and Mdm2 is accessible to small molecules based on its dimension, concavity and hydrophobicity of the binding site. See Fry, D.; Vassilev, L. J. Mol. Med. 2005, 83, 955-963. While p53-Mdm2 antagonists have been discovered by different analytical techniques, including high throughput screening (HTS), computational HTS and structure-based design, the present inventors used of a web-based and structure-based design tool, “ANCHOR.QUERY,” which led to the discovery and optimization of new potent p53-Mdm2 antagonists, based on the Ugi multicomponent reaction.